Recent Advances in the Microbial Synthesis of Hemoglobin.

Saccharopolyspora erythraea is used for industrial erythromycin production. To explore the physiological role of intracellular energy state in metabolic regulation by S. erythraea, we initially overexpressed the F1 part of the endogenous F1F0-ATPase in the high yielding erythromycin producing strain E3. The F1-ATPase expression resulted in lower [ATP]/[ADP] ratios, which was accompanied by a strong increase in the production of a reddish pigment and a decreased erythromycin production. Subsequent transcriptional analysis revealed that the lower intracellular [ATP]/[ADP] ratios exerted a pleotropic regulation on the metabolism of S. erythraea. The lower [ATP]/[ADP] ratios induced physiological changes to restore the energy balance, mainly via pathways that tend to produce ATP or regenerate NADH. The F1-ATPase overexpression strain exhibited a state of redox stress, which was correlated to an alteration of electron transport at the branch of the terminal oxidases, and S. erythraea channeled the enhanced glycolytic flux toward a reddish pigment in order to reduce NADH formation. The production of erythromycin was decreased, which is in accordance with the net ATP requirement and the excess NADH formed through this pathway. Partial growth inhibition by apramycin increased the intracellular [ATP]/[ADP] ratios and demonstrated a positive correlation between [ATP]/[ADP] ratios and erythromycin synthesis. Finally, overexpression of the entire F1F0-ATPase complex resulted in 28% enhanced erythromycin production and markedly reduced pigment synthesis in E3. The work illustrates a feasible strategy to optimize the distribution of fluxes in secondary metabolism.

/pdf/cofactor-engineering-redirects-secondary-metabolism-and-14znh1kk10.pdf

Cofactor Engineering Redirects Secondary Metabolism and Enhances Erythromycin Production in Saccharopolyspora erythraea.

Vitreoscilla hemoglobin (VHb), the first discovered bacterial hemoglobin, is a soluble heme-binding protein with a faster rate of oxygen dissociation. Since it can enhance cell growth, product synthesis and stress tolerance, VHb has been widely applied in the field of metabolic engineering for microorganisms, plants, and animals. Especially under oxygen-limited conditions, VHb can interact with terminal oxidase to deliver enough oxygen to achieve high-cell-density fermentation. In recent years, with the development of bioinformatics and synthetic biology, several novel physicochemical properties and metabolic regulatory effects of VHb have been discovered and numerous strategies have been utilized to enhance the expression level of VHb in various hosts, which greatly promotes its applications in biotechnology. Thus, in this review, the new information regarding structure, function and expressional tactics for VHb is summarized to understand its latest applications and pave a new way for the future improvement of biosynthesis for other products.

https://www.mdpi.com/2076-2607/9/7/1455/pdf

Recent Advances in the Physicochemical Properties and Biotechnological Application of Vitreoscilla Hemoglobin.

Efficient cell factories are the core of industrial biotechnology. In recent years, synthetic biology develops rapidly, and more and more modified microbial cell factories are employed in industrial biotechnology. ATP plays vital roles in biosynthesis, metabolism regulation, and cellular maintenance. Regulating cellular ATP supply can effectively modify cellular metabolism. This paper presents a review of recent studies on the regulation of the intracellular ATP supply and its application in industrial biotechnology. Detailed strategies for regulating the ATP supply and the resulting impact on bioproduction are introduced. It is observed that regulating the cellular ATP supply can provide great possibilities for making microbial cells into efficient factories. Future perspectives for further understanding the function of ATP are also discussed.

Regulation of intracellular ATP supply and its application in industrial biotechnology.

Cofactors are crucial chemicals that maintain cellular redox balance and drive the cell to do synthetic and catabolic reactions. They are involved in practically all enzymatic activities that occur in live cells. It has been a hot research topic in recent years to manage their concentrations and forms in microbial cells by using appropriate techniques to obtain more high-quality target products. In this review, we first summarize the physiological functions of common cofactors, and give a brief overview of common cofactors acetyl coenzyme A, NAD(P)H/NAD(P)+, and ATP/ADP; then we provide a detailed introduction of intracellular cofactor regeneration pathways, review the regulation of cofactor forms and concentrations by molecular biological means, and review the existing regulatory strategies of microbial cellular cofactors and their application progress, to maximize and rapidly direct the metabolic flux to target metabolites. Finally, we speculate on the future of cofactor engineering applications in cell factories. Graphical Abstract

/pdf/application-of-cofactors-in-the-regulation-of-microbial-3iifg2l5.pdf

Application of cofactors in the regulation of microbial metabolism: A state of the art review

In the biosynthesis of S-adenosylmethionine (SAM) in baker’s yeast (Saccharomyces cerevisiae), ATP functions as both a precursor and a driving force. However, few published reports have dealt with the control of ATP concentration using genetic design. In this study we have adopted a new ATP regulation strategy in yeast for enhancing SAM biosynthesis, including altering NADH availability and regulating the oxygen supply. Different ATP regulation systems were designed based on the introduction of water-forming NADH oxidase, Vitreoscilla hemoglobin, and phosphite dehydrogenase in combination with overexpression of the gene SAM2. Via application of this strategy, after 28 h cultivation, the SAM titer in the yeast strain ABYSM-2 reached a maximum level close to 55 mg/L, an increase of 67% compared to the control strain. The results show that the ATP regulation strategy is a valuable tool for SAM production and might further enhance the synthesis of other ATP-driven metabolites in yeast.

Enhanced S-Adenosylmethionine Production by Increasing ATP Levels in Baker's Yeast ( Saccharomyces cerevisiae).

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Enhanced S-Adenosylmethionine Production by Increasing ATP Levels in Baker's Yeast ( Saccharomyces cerevisiae).